Patent GB-814065-A (GB)
Title: Substituted phenoselenazine compounds
Filed: 1957-12-31
Abstract: The invention comprises compounds of the general formula <FORM:0814065/IV (b)/1> and non-toxic acid addition salts thereof (wherein Y is a hydrogen or halogen atom or a trifluoromethyl, lower alkyl or lower alkoxy group, A is a divalent alkylene chain containing 2 to 6 carbon atoms, R1 and R2 individually are hydrogen atoms or lower alkyl groups, or when taken together with the nitrogen atom to which they are attached form a monocyclic five- or six-membered ring, such as pyrrolidinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl or substituted piperazinyl), and the preparation thereof by condensing a 10-unsubstituted phenoselenazine with a reactive tertiary amino alkyl ester (e.g. a halide or a sulphonic or sulphuric ester). The compounds of the invention can alternatively be prepared by modifying an alkyl chain which has a reactive terminal group such as a halogen atom, a carboxy, tosylate, aldehydo or cyano group, and which chain is attached to the 10-position of the parent phenoselenazine.  The lower alkyl and lower alkoxy groups do not contain more than four carbon atoms, preferably not more than two carbon atoms.  The term substituted piperazinyl includes such moieties as N-lower-alkyl, N-(o -hydroxy-lower-alkyl) -, N - (o  - di - lower - alkylamino - lower - alkyl) -, N - (o  - hydroxy - lower - alkoxy-lower - alkyl) -, 2,5 - dimethyl -, N - lower-alkyl - 2,5 - dimethyl -, N - acyl - or N - (o -acyloxy - lower - alkyl) - piperazinyl.  The compounds have pharmaceutical properties.  In examples: (1) 2-chlorophenoselenazine is reacted with 3-chloro-1-dimethylaminopropane to give 2 - chloro - 10 - (31 - dimethylaminopropyl)-phenoselenazine, from which the hydrochloride and maleate salts are prepared; (2) 2-chloro-10-[21 - methyl - 31 - (N - methylpiperazinyl)-propyl) phenoselenazine and its citrate are prepared from 2 - chlorophenoselenazine and 3-chloro - 2 - methyl) - 1 - (N - methylpiperazinyl)-propane; (3) 10 - (31 - dimethyl - aminopropyl) phenoselenazine and its hydrochloride and maleate are prepared from phenoselenazine and 3 - chloro - 1 - dimethylaminopropane; (4) 10-(21-cyanoethyl)-phenoselenazine is reduced by lithium aluminium hydride to give 10-(31-aminopropyl) - phenoselenazine; (5) 10 - (31 - methylbenzylaminopropyl)-phenoselenazine is treated with hydrogen, palladium-charcoal catalyst, then maleic acid to give 10-(31-methylaminopropyl) - phenoselazine maleate; (6) 10 - (31-piperazinylpropyl)-phenoselenazine is prepared from 10(31-chloropropyl) - phenoselenazine and piperazine; (7) 10 - [31 - (N - acetoxyethylpiperazinyl) propyl]-phenoselenazine dimaleate is prepared from the product of (6) and b -bromo-ethylacetate and maleic acid; (8) the product of (6) is treated with b -bromoethanol and mandelic acid to give 10 - [31 - (N - b  - hydroxyethyl piperazinyl) - propyl] - phenoselenazine dimandelate; and (9) 10 - [31 - (N - b  - hydroxyethoxyethyl - piperazinyl) - propyl] - phenoselenazine dimandelate is prepared from the product of (6), 2 - bromo - 21 - hydroxyethyl ether and mandelic acid.  Similarly prepared are: 10 - [31 - (N - diethylaminoethyl piperazinyl)-propyl] - phenoselenazine and its trihydrobromide; 10 - (21 - diethylaminoethyl) - 2 - trifluoromethyl phenoselenazine, and its tartrate; 10 - (31 - dimethylaminopropyl) - 2 - trifluoromethyl phenoselenazine; 10 - (31 - dimethy) aminopropyl) - 1 - methyl phenoselenazine and its maleate; 3 - methoxy - 10 - [3 - (N,211,511-trimethylpiperazinyl) - propyl] - phenoselenazine and its ethanedisulphonate; 10-(51-dimethylaminopentyl) - 3 - methoxy phenoselenazine; 4 - chloro - 10 - (31 - dimethylamino - propyl)-phenoselenazine and its maleate; 3-ethyl-10-(31 - N - pyrrolidinylpropyl) - phenoselenazine and its salicylate; 2-chloro-10-(21-N-piperazinylethyl) - phenoselenazine; 2 - chloro - 10-[21 - (N - ethylpiperazinyl) - ethyl] phenoselenazine, 10 - [21 - (N - butylpiperazinyl)-ethyl] - 2 - chlorophenoselenazine and its dihydrobromide and dimaleate; 10-(31-dimethylaminopropyl) - 2 - isopropoxyphenoselenazine maleate; 10 - [2,121 - dimethyl - 31 - (N-piperidyl) - propyl] - 2 - trifluoromethylphenoselenazine; 2 - bromo - 10 - [21 - (N - morpholinyl) isopropyl] - phenoselenazine maleate; 10 - (31 - N - thiomorpholinylpropyl) - phenoselenazine; 1 - butyl - 10 - [31 - (N - methylpiperazinyl) - propyl] - phenoselenazine dimandelate; 2 - methoxy - 10 - [21 - methyl - 31-(N - methylpiperazinyl) - propyl] - phenoselenazine and its dimaleate; 10-[21-(N-ethylpiperazinyl) - ethyl] - 2 - methylphenoselenazine and its dimaleate; 2-chloro-10-[31-N-methylpiperazinyl) - propyl] - phenoselenazine; 10-[31-acetoxyethylpiperazinyl) - propyl] - 2 - chlorophenoselenazine dimaleate, 2-chloro-10-[2-N-hydroxy - ethylpiperazinyl) - propyl] - phenoselenazine; 10 - (31 - dimethylamino - 21-methyl - propyl) - 2 - trifluoromethyl phenoselenazine and its maleate; and 10-[21-methyl-31 - (N - methylpiperazinyl) - propyl] - 2 - trifluoromethylphenoselenazine. Also prepared are: 10 - (31 - butylaminopropyl) - 2 - chlorophenoselenazine and its maleate from 2-chloro - 10 - (31 - hydroxypropyl) - phenoxlenazine p - toluenesulphonate and butylamine; 10 - (31 - aminopropyl) - 2 - chlorophenoselenazine; 2 - chloro - 10 - (31 - ethylaminopropyl)-phenoselenazine; 2 - chloro - 10 - (31 - N - piperazinyl propyl)-phenoselenazino; and 2-chloro-10 - [31 - N - (2,5 - dimethylpiperazinyl) - propyl]-phenoselenazine.  Further salts specified are those prepared from: fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulphonic, acetic, propionic, gluconic, lactic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, glutamic, benzenesulphonic, theophylline acetic sulphuric, sulphamic, phosphoric and nitric acids, and from 8-chlorotheophylline and 8-bromotheophylline). Phenoselenazines, unsubstituted in the 10 position, are prepared by heating Y-substituted diphenyl amines with selenium or preferably selenium monochloride.  Exemplified is the preparation of: 2-chlorophenoselenazine, phenoselenazine, 2 - trifluoromethylphenoselenazine, 1-methylphenoselenazine, 3 - methoxyphenoselenazine, 4 - chlorophenoselenazine; 3 - ethylphenoselenazine, 2 - isopropoxyphenoselenazine, 2 - bromophenoselenazine, 1 - butylphenoselenazine, 2 - methoxyphenoselenazine, 2 - methylphenoselenazine.  10 - (21 - cyanoethyl) - phenoselenazine is prepared by reacting phenoselenazine with acrylonitrile and benzyltrimethyl ammonium hydroxide; 10 - (31 - benzylaminopropyl) - phenoselenazine is prepared by treating phenoselenazine with benzaldehyde, hydrogen and palladium-charcoal catalyst; treatment of the compound with formaldehyde and formic acid gives 10 - (31 - methylbenzylaminopropyl) - phenoselenazine; 10 - (31 - chloropropyl) - phenoselenazine is prepared from phenoselenazine and 1 - bromo - 3 - chloropropane; 10 - [21 - (N-acetylpiperazinyl) - ethyl] - 2 - chlorophenoselenazine is prepared by acylating 2-chloro-10-(21-N-piperazinylethyl)-phenoselenazine with acetyl chloride; 2 - chloro - 10 - (31 - hydroxypropyl)-phenoselenazine p - toluenesulphonate is prepared by treating the sodio derivative of 2-chlorophenoselenazine with g -bromopropyl tetrahydropyranyl ether, refluxing the product in hydrochloric acid and acylating the crude g -hydroxy compound with p-toluenesulphonyl chloride.